Citations

Abstract Dementia is associated with altered resting-state connectivity, measures of which could aid in its early detection and monitoring. High-density diffuse optical tomography (HD-DOT) is well suited to detect these alterations at scale due to its numerous practical advantages, but it has not yet been applied to dementia. In this study, we investigated resting-state functional connectivity across the prefrontal cortex in individuals with mild cognitive impairment (MCI, n = 22), Alzheimer’s disease (AD, n = 21), and in healthy controls (n = 22). A graph theoretical approach was taken to characterise both global and local patterns of prefrontal connectivity over a 5-minute resting period. We found that individuals with MCI exhibited denser and stronger networks with shorter path lengths, which normalised in AD, accompanied by a redistribution of network hubs that were less stable. These results perhaps reflect the recruitment of additional connections in the early stages of pathology to maintain short-term network stability, which is ultimately associated with less efficient and more fragmented network organisation in later stages. Following the demonstration of HD-DOT’s capacity to detect differences between healthy ageing and AD-type cognitive impairment, this work opens up new possibilities for the use of optical imaging in the study of this clinical population and HD-DOT’s potential for scalable clinical use.

Study Design: Retrospective cohort. Objective: This study aims to assess the effects of CT-based subsidence on lumbar sagittal alignment and patient-reported outcome measures (PROMs) after transforaminal lumbar interbody fusion (TLIF), and to determine if subsidence and cage properties are independent predictors of postoperative changes in regional lordosis. Summary of Background Data: Subsidence is a well-known complication following interbody fusion and has previously been associated with recurrence of preoperative symptoms and higher reoperation rates. There is incomplete evidence to characterize the effects of subsidence on lumbar alignment and PROMs following TLIF. Methods: All adult patients who underwent 1- or 2-level TLIF at a multi-institutional academic center between 2017 and 2019 were retrospectively identified. Interbody subsidence at the superior and inferior endplate of each TLIF level was directly measured on both coronal and sagittal CT scans obtained between 6 months and 1 year postoperatively. Patients were grouped based on the maximum subsidence at each operative level: mild-moderate (<4 mm) or severe (≥4 mm). Preoperative, immediate (<3 mo), and intermediate (>6 mo) postoperative radiographic outcomes (local and global lumbar alignment) and PROMs (VAS Back, Oswestry Disability Index, PROMIS Physical Function and Mood) were collected. Univariate and multivariate analysis compared patient demographics, surgical factors, and changes in radiographic measures and PROMs across subsidence groups. Multiple linear regression analyzed independent effects of subsidence and cage characteristics on alignment. Results: Sixty-seven patients with 85 unique fusion levels were included (55 with mild-moderate subsidence, 30 with severe subsidence). Levels with severe subsidence demonstrated significantly less regional lordosis at final follow-up than nonseverely subsided levels (6.4 vs. 9.1 degrees, P =0.032). No PROM significantly differed between severe and nonsevere subsidence subgroups. Linear regression analysis revealed that severe subsidence was a strong independent predictor of regional lordosis ( P =0.029) at final follow-up. Conclusions: Severe subsidence negates perioperative improvements in regional lordosis following TLIF, while changes in regional alignment are maintained in the absence of severe subsidence. Level of Evidence: Level III.

RET fusions appear in 1%-2% of non–small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385 ) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET -altered NSCLC and RET fusion–positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion–positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion–positive NSCLCs, confirming previous findings with longer follow-up.

Objective: The identification of reliable biomarkers in trauma patients (pts) remains a clinical challenge. Nucleosomes, which are DNA wrapped around histone protein cores, have been used as reliable markers for quantification in sepsis, acute respiratory distress syndrome, and lymphoma. We hypothesized that: 1) levels of circulating nucleosomes quantified after traumatic injury, specifically histone H3.1 and its citrullinated R8 posttranslation modification (H3R8 Cit), would be increased after trauma and 2) that levels of circulating nucleosomes would be further, increased in pts who went on to develop venous thromboembolism (VTE), as these nucleosomes may be clot-enhancing mediators. Methods: Trauma pts presenting to a Level I trauma center were evaluated for inclusion in a prospective case-cohort study, and citrated blood samples were collected within 12 hours of injury. Pts were followed for up to 90 days and VTE occurrence was confirmed via autopsy or imaging. Pts who developed incident, symptomatic VTE, and those who did not develop VTE were selected at a 1:3 ratio. The effect of trauma was assessed by comparison with healthy volunteer samples. Circulating nucleosomes were quantified using Nu.Q H3.1 and Nu.Q H3R8 Cit assays. Data are presented as median [interquartile range] or n (%), with Wilcoxon Rank-Sum or chi-squared test performed between trauma pts who developed symptomatic VTE versus those who did not, with a P value < 0.05 as statistically significant. Results: A total of 639 trauma pts were analyzed [51 years (33, 65), 71.0% male, 94.1% blunt, injury severity scores 17 (9, 27)]. Both H3.1 [359.7 (58.4, 1769.3) vs. 21.5 (15.3, 26.6) ng/mL, P < 0.001] and H3R8 Cit levels [209.4 (45.4, 665.5) vs. 22.3 (16.2, 28.9) ng/mL, P < 0.001] were greater in trauma pts than in 10 healthy volunteers. The 160 pts with VTE were then compared with 479 without VTE. VTE pts had a median time to VTE of 8.5 days, with 91 developing symptomatic deep venous thrombosis, 48 with pulmonary embolism, and 21 with both deep venous thrombosis and pulmonary embolism. No significant differences were found in age, sex, or mechanism between pts with or without VTE. However, VTE pts had higher injury severity scores [24 (14, 34), 14 (9, 24), P < 0.001] and body mass index [29.1 (24.3, 34.2), 27.6 (24.2, 32.0) kg/m 2 , P = 0.037]. A greater percentage of VTE pts underwent surgery requiring general anesthesia (53.1%, 34.0%, P < 0.001) and received blood transfusions within 24 hours of injury (51.9%, 24.0%, P < 0.001). H3.1 levels were significantly greater in trauma pts who developed VTE compared with those who did not [828.4 (112.0, 3186.5), vs. 276.7 (50.3, 1237.0) ng/mL, P < 0.001], as were H3R8 Cit levels [350.4 (77.4, 729.5), vs. 189.2 (40.8, 632.6) ng/mL, P = 0.005]. No differences in levels of H3.1 and H3R8 Cit were found between early (diagnosed day 0–7 after injury) and late (diagnosed > day 7) VTE. Conclusions: Levels of the H3.1 and H3R8 Cit nucleosomes are elevated early after traumatic injury, especially in those who developed VTE. These findings underscore the importance of understanding the pathophysiology of nucleosomes in inducing VTE and their role as biomarkers

Single ventricle is a rare congenital heart defect involving one functional ventricle, and imaging is essential for classification, functional assessment, anomaly detection, and guiding management.

Precis: This retrospective multicentre study of 77 NTG eyes undergoing phacoemulsification and Hydrus implantation showed a sustained reduction in medication burden, while maintaining IOP levels. Complications were rare and nonsight-threatening. Purpose: To evaluate 36-month outcomes of combined phacoemulsification and Hydrus Microstent implantation (Phaco-Hydrus) in eyes with normal tension glaucoma (NTG). Methods: This multicentre retrospective study included 77 NTG eyes from Singapore and Canada that underwent Phaco-Hydrus between 2014 and 2023. Primary outcomes were changes in intraocular pressure (IOP) and medication burden, and cumulative success probabilities from Kaplan-Meier (KM) analyses. Longitudinal changes were analysed using generalized estimating equations. Results: Of 77 eyes, 31 completed 36 months of follow-up. Mean baseline IOP and medications was 13.5±2.5 mm Hg and 1.7±0.9, respectively. No significant reductions in IOP were observed. A sustained reduction in medication use was observed at all follow-up timepoints ( P ≤0.001). At 36 months, medication use decreased by −0.7±0.2 [adjusted mean difference±SE of the mean [SEM]]. Proportion of medication-free eyes increased from 7.8% (n=6/77) at baseline to 45.2% (n=14/31) at 36 months. Cumulative success probabilities varied widely based on definitions. When defined as a decrease in ≥1 medication from baseline without an increase in IOP, or IOP ≤15 mm Hg and reduced ≥20% from baseline while medication-free, and no additional laser or incisional glaucoma surgery, this was 40.7% at 36 months. No visual field mean deviation progression was detected. Adverse events were infrequent and nonsight-threatening. Conclusion: In eyes with NTG, Phaco-Hydrus may offer a greater role in medication reduction or achieving a medication-free status over 36 months, rather than absolute IOP reduction.

Abstract In epilepsy patients lacking magnetic resonance imaging‐visible lesions such as focal cortical dysplasia (FCD), surgical resections target regions with abnormal electroencephalographic (EEG) activity. However, histopathological identification of subtle cortical architectural abnormalities in these specimens remains challenging. We investigated whether artificial intelligence (AI)‐based morphometric and spatial analysis of NeuN‐stained cortical sections could detect neuronal architectural disorganization in epilepsy resections, including regions without definitive histologic dysplasia. Whole slide images were generated from 83 FCD regions and 19 neurologically normal autopsy controls. Regions of interest were annotated in QuPath as FCD, FCD‐adjacent, FCD‐distant, apparently normal (abnormal EEG without histologic dysplasia), and true normal (autopsy controls). NeuN‐positive neurons were detected using QuPath (90% sensitivity, 12% false positive rate). Spatial and morphometric features—including neuronal clustering, distribution inhomogeneity, and nuclear morphology—were extracted and used to train a multinomial, Least Absolute Shrinkage and Selection Operator‐regularized regression classifier. The classifier achieved 70.6% accuracy in subregion classification and 88.2% accuracy in overall specimen diagnosis. Notably, regions with abnormal EEG but lacking histologic dysplasia exhibited quantifiable architectural disorganization similar to those seen in areas adjacent to FCD and distinct from control tissue. AI‐driven analysis of neuronal morphology and spatial distribution reveals subtle cortical disorganization in epilepsy resections, including in histologically ambiguous regions. Further investigation is warranted to determine if this methodology can enhance the diagnostic yield of neuropathological evaluation and support more precise surgical targeting in epilepsy.

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The accurate prediction of motor progression in Parkinson’s disease (PD) remains a major clinical challenge that limits personalized treatment planning and efficient clinical trial design. In this study, we developed and validated a machine-learning framework integrating a targeted panel of plasma proteins measured by Olink proximity extension assays with clinical variables to stratify patients according to their progression risk. We analyzed baseline plasma samples from 211 early-stage PD patients enrolled in the Parkinson’s Progression Markers Initiative (PPMI) cohort using four targeted Olink panels, from which 28 circulating proteins were retained after quality-control filtering. Patients were classified as rapid or slow progressors based on their annualized change in MDS-UPDRS Part III scores. Among the algorithms tested, Random Forest achieved the highest discriminative performance with an area under the receiver operating characteristic curve (AUC) of 0.751 (95% CI: 0.684–0.811), which exceeded that of clinical predictors alone (AUC 0.666). The integration of targeted proteomic and clinical features further improved model performance (AUC 0.773; p = 0.009). Nested cross-validation confirmed minimal optimistic bias (AUC 0.743). To enhance clinical interpretability, we applied SHapley Additive exPlanations (SHAP) analysis, which identified interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor A (VEGF-A) as the most influential predictors. SHAP feature rankings were highly stable across cross-validation folds (mean Spearman ρ = 0.91). The robustness of these findings was confirmed through sensitivity analyses using extreme quartile comparisons (AUC 0.823), treatment-naïve subgroup analysis (AUC 0.738), and a clinically anchored outcome definition based on the minimal clinically important difference (AUC 0.739). A decision curve analysis demonstrated a net clinical benefit across threshold probabilities of 0.25–0.70. Our results establish targeted plasma protein profiling combined with interpretable machine learning as a promising tool for PD motor progression risk stratification, with potential applications in individualized patient counseling regarding motor prognosis and the selection of candidates for disease-modifying trials.